A. Octopamine and Octopamine Receptors
Octopamine (OA) was first discovered over 35 years ago in the posterior salivary gland of the octopus (V. Erspamer and G. Boretti, Arch. Int. Pharmaco. Ther. 88: 926-322 (1951)). Although similar to norepinephrine (NE) in structure, OA has very little activity as a sympathomimetic when injected into mammals (A. Lands and J. Grant, J. Pharm. Exptl. Therap. 106: 341-345 (1952)) and, compared with NE, is present in very low concentrations in vertebrate tissues (Y. Kakimoto and M;. Armstrong, J. Biol. Chem. 237: 422-427 (1962)). Relatively little attention was paid to OA until early 1970's, when Molinoff and Axelrod reported that OA was present in much higher concentrations in invertebrates, particularly in invertebrate nerve tissue (P. B. Molinoff and J. Axelrod, J. Neurochem. 19: 157-163 (1972)).
In 1973, the first identification of an OA receptor was reported (J. A. Nathanson "Cyclic AMP: A Possible Role in Insect Nervous System Function", (Ph.D. Thesis) (1973); J. A. Nathanson and P. Greengard, Science, 19: 308-310 (1973)). Because this receptor was present in highest concentrations in insect nerve cord, it was postulated that OA might function as a neurotransmitter. Furthermore, because these receptors were undetectable in mammalian tissues, it was also postulated that the neurotransmitter function of OA might be largely restricted to invertebrates (J. A. Nathanson "Cyclic AMP: A Possible Role in Insect Nervous System Function", (Ph.D. Thesis) (1973); J. A. Nathanson and P. Greengard, Science, 19: 308-310 (1973); J. A. Nathanson, Trace Amines and the Brain: Eds. Marcel Dekker, pp. 161-190 (1976)). At about the same time, Kravitz and coworkers (B. Wallace et al., Brain Res. 349-55 (1974)) independently reported the presence of OA-containing neurons in crustacea, and, somewhat later, Hoyle reported evidence suggesting the presence of large OA neurons in insect ganglia (G. Hoyle, J. Exp. Zool 193: 425-31 (1975)). Subsequent work by a number of investigators has established the role of OA, not only as a neurotransmitter, but also as a neuromodulator and circulating neurohormone in insects and acarines (for review see I. Orchard, Can. J. Zool, 60: 659-69 (1982); H. A. Robertson and A. V. Juorio, Int. Rev. Neurobiol. 19: 173-224 (1976)). Indeed, OA plays a pervasive role in regulating many areas of insect physiology, including carbohydrate metabolism, lipid mobilization, hematocyte function, heart rate, peripheral muscle tension and excitability, and behavior. The functions that OA carries out in insects appear analogous to those carried out by norepinephrine (NE) and epinephrine (EPI) in vertebrates. This has led to the suggestion that, during evolution, there may have been a divergence in the use of these amines between the two arms of the animal kingdom (H. A. Robertson and A. V. Juorio, Int. Rev. Neurobiol. 19: 173-224 (1976); A. V. Robertson and A. V. Juorio, J. Neurochem. 28: 573-79 (1977); J. A. Nathanson, Physiological Reviews 57: 158-256 (1977)).
Analogous to the action of NE and EPI in vertebrates, many of the effects of OA in invertebrates are mediated by cyclic AMP (J. A. Nathanson and P. Greengard, Science 19: 308-310 (1973); J. A. Nathanson, Physiological Reviews 57: 158-256 (1977); H. Robertson and J. Steele, J. Neurochem 19: 1603-06 (1972); A. Harmar and A. Horn, Mol. Pharmacol. 13: 512-20 (1976); C. Lingle et al., Handbook of Exptl. Pharmacology, (J. Kebabian & J. Nathanson, eds. ), pp. 787-846 (1982)). OA stimulates production of cyclic AMP through activation of OA-sensitive (G.sub.s protein-coupled) adenylate cyclase (J. A. Nathanson, J. Cyclic Nucleotide and Protein Phosphor. Res. 10: 157-66 (1985)). In 1979, it was found that the firefly light organ, in which OA mediates neural control of light emission (A. D. Carlson, Advances Insect Physiol. 6: 51-96 (1969); J. F. Case and L. G. Strause, Bioluminescence in Action (P. J. Herring, ed.), pp. 331-366 (1978)), has a virtually pure population of OA receptors present in enormous quantity, with no evidence of adenylate cyclases activated by other hormones (J. A. Nathanson, Science 203: 65-8 (1979); J. A. Nathanson and E. Hunnicutt, J. Exp. Zool. 208: 255-62 (1979a)). Thereafter, the first detailed pharmacological characterization of G.sub.s -linked OA receptors was carried out in the absence of other amine receptors (J. A. Nathanson, Science 203: 65-8 (1979); J. A. Nathanson and E. Hunnicutt, J. Exp. Zool. 208: 255-62 (1979a); J. A. Nathanson, Proc. Natl. Acad. Sci. U.S.A. 82: 599-603 (1985b); Nathanson, J. A., in Insect Neurochemistry and Neurophysiology, Borkovec, A., et al., eds., Humana: Clifton, N.J., pp. 263-266 (1986); Nathanson, J. A., et al., Neurosci. Abstr. 5:346 (1979)). More recently, a new chemical class of potent OA receptor agonists has been characterized, the phenyliminoimidazolidines (PIIs) (Nathanson, J. A., Proc. Natl. Acad. Sci. U.S.A. 82: 599-603 (1985); Nathanson, J. A., Mol. Pharmacol. 28: 254-268 (1985)). With the PIIs and other compounds, it has been possible to distinguish clearly the characteristics of OA receptors from those of mammalian adrenergic, dopaminergic, and serotonergic receptors.
Overactivation of the OA system in insects and acarines leads to behavioral and physiological abnormalities that have pestistatic and pesticidal consequences. One way to cause OA overactivation, and thereby take advantage of this system for pesticide development, is to directly stimulate OA receptor proteins.
Analogous to the octopamine neurotransmitter system is the cholinergic system, where the plant alkaloid nicotine exerts natural pesticidal effects through excessive activation of acetylcholine (ACh) receptors. As is well known, for pesticide development it has turned out that, more effective than cholinergic agonists, are the reversible and irreversible acetylcholinesterase inhibitors. Acetylcholinesterase (AChE) catalyzes the hydrolysis of the neurotransmitter ACh to choline and acetate. If AChE is inhibited by a pesticide, normal inactivation of ACh is blocked, and ACh accumulates to abnormally high levels. This causes overactivation of ACh receptors, indirectly, through inhibition of neurotransmitter degradation. We have recently discovered that an analogous site of action exists for the OA system. Because of OA's selectivity for invertebrates, agents affecting this site will have reduced toxicity for vertebrates.